PT  - JOURNAL ARTICLE
AU  - Seiji Sato
AU  - Xi-Ping Huang
AU  - Wes Kroeze
AU  - Bryan L Roth
TI  - Discovery and characterization of novel GPR39 agonists allosterically modulated by zinc
AID  - 10.1124/mol.116.106112
DP  - 2016 Jan 01
TA  - Molecular Pharmacology
PG  - mol.116.106112
4099  - http://molpharm.aspetjournals.org/content/early/2016/10/17/mol.116.106112.short
4100  - http://molpharm.aspetjournals.org/content/early/2016/10/17/mol.116.106112.full
AB  - In this study, we identified two previously described kinase inhibitors-- LY2784544 and GSK2636771-- as novel GPR39 agonists by unbiased small-molecule-based screening using a βarrestin recruitment screening approach (PRESTO-Tango). We characterized the signaling of LY2784544 and GSK2636771 and compared it with a previously described "GPR39-selective" agonist GPR39-C3 at both canonical and non-canonical signaling pathways. Unexpectedly, all three compounds displayed probe-dependent and pathway-dependent allosteric modulation by zinc. These findings reveal an unexpected role of zinc as an allosteric potentiator of small-molecule-induced activation of GPR39.